Evolutionary Chemistry (EC) is a drug discovery methodology developed to efficiently identify lead pharmaceutical compounds from enormous but focused small molecule libraries. The methodology involves biocatalyzed small molecule library assembly, lead compound selection through the application of evolutionary pressures, and amplification of selected compounds. The frequency at which EC-derived drug leads become drugs would be significantly increased if the lead compound selection components of this methodology demanded not only high affinity for the drug target, but also other drug-like properties. For lead compounds that survive functional screens to become drug candidates, favorable absorption, distribution, metabolism, elimination (ADME), and toxicity properties are all critical determinants of clinical success. The goal of the proposed research is to develop and validate ADME-predictive lead compound selection methods that can be integrated into the EC technology. The lead compound selection methods to be investigated would demand that EC-derived lead compounds have, in addition to high drug target affinity, favorable membrane permeability, serum protein affinity, and metabolism properties. The long-term objective of this research endeavor is to meet medical needs through the application of this improved technology to important drug targets.